title: Hypoxia induces phenotypic plasticity and therapy resistance in melanoma via the tyrosine kinase receptors ROR1 and ROR2.
abstract: An emerging concept in melanoma biology is that of dynamic, adaptive phenotype switching, where cells switch from a highly proliferative, poorly invasive phenotype to a highly invasive, less proliferative one. This switch may hold significant implications not just for metastasis, but also for therapy resistance. We demonstrate that phenotype switching and subsequent resistance can be guided by changes in expression of receptors involved in the noncanonical Wnt5A signaling pathway, ROR1 and ROR2. ROR1 and ROR2 are inversely expressed in melanomas and negatively regulate each other. Furthermore, hypoxia initiates a shift of ROR1-positive melanomas to a more invasive, ROR2-positive phenotype. Notably, this receptor switch induces a 10-fold decrease in sensitivity to BRAF inhibitors. In patients with melanoma treated with the BRAF inhibitor vemurafenib, Wnt5A expression correlates with clinical response and therapy resistance. These data highlight the fact that mechanisms that guide metastatic progression may be linked to those that mediate therapy resistance.
  
  
  CONCLUSIONS
  These data show for the fi rst time that a single signaling pathway, the Wnt signaling pathway, can effectively guide the phenotypic plasticity of tumor cells, when primed to do so by a hypoxic microenvironment. Importantly, this increased Wnt5A signaling can give rise to a subpopulation of highly invasive cells that are intrinsically less sensitive to novel therapies for melanoma, and targeting the Wnt5A/ROR2 axis could improve the efficacy and duration of response for patients with melanoma on vemurafenib.
authors.affiliation: 1Tumor Metastasis and Microenvironment Program and 2Molecular and Cellular Oncogenesis Program, The Wistar Institute; 3Abramson Cancer Center, University of Pennsylvania, Philadelphia; 4Lehigh Valley Health Network, Allentown, Pennsylvania; 5The National Institute on Aging, NIH, Baltimore, Maryland; and 6Dana-Farber/Harvard Cancer Center, Boston, Massachusetts.
authors.forename: Michael P
authors.initials: MP
authors.lastname: O'Connell
authors.forename: Katie
authors.initials: K
authors.lastname: Marchbank
authors.forename: Marie R
authors.initials: MR
authors.lastname: Webster
authors.forename: Alexander A
authors.initials: AA
authors.lastname: Valiga
authors.forename: Amanpreet
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authors.lastname: Kaur
authors.forename: Adina
authors.initials: A
authors.lastname: Vultur
authors.forename: Ling
authors.initials: L
authors.lastname: Li
authors.forename: Meenhard
authors.initials: M
authors.lastname: Herlyn
authors.forename: Jessie
authors.initials: J
authors.lastname: Villanueva
authors.forename: Qin
authors.initials: Q
authors.lastname: Liu
authors.forename: Xiangfan
authors.initials: X
authors.lastname: Yin
authors.forename: Sandy
authors.initials: S
authors.lastname: Widura
authors.forename: Janelle
authors.initials: J
authors.lastname: Nelson
authors.forename: Nivia
authors.initials: N
authors.lastname: Ruiz
authors.forename: Tura C
authors.initials: TC
authors.lastname: Camilli
authors.forename: Fred E
authors.initials: FE
authors.lastname: Indig
authors.forename: Keith T
authors.initials: KT
authors.lastname: Flaherty
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Wargo
authors.forename: Dennie T
authors.initials: DT
authors.lastname: Frederick
authors.forename: Zachary A
authors.initials: ZA
authors.lastname: Cooper
authors.forename: Suresh
authors.initials: S
authors.lastname: Nair
authors.forename: Ravi K
authors.initials: RK
authors.lastname: Amaravadi
authors.forename: Lynn M
authors.initials: LM
authors.lastname: Schuchter
authors.forename: Giorgos C
authors.initials: GC
authors.lastname: Karakousis
authors.forename: Wei
authors.initials: W
authors.lastname: Xu
authors.forename: Xiaowei
authors.initials: X
authors.lastname: Xu
authors.forename: Ashani T
authors.initials: AT
authors.lastname: Weeraratna
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D006801:Humans; D007211:Indoles / Q000627:therapeutic use*; D008545:Melanoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism* / Q000556:secondary; D008546:Melanoma, Experimental; D051379:Mice; D008819:Mice, Nude; D009362:Neoplasm Metastasis; D010641:Phenotype; D057050:Receptor Tyrosine Kinase-like Orphan Receptors / Q000235:genetics / Q000378:metabolism*; D013449:Sulfonamides / Q000627:therapeutic use*; D000077484:Vemurafenib; D060449:Wnt Signaling Pathway
chemical_list: D000970:Antineoplastic Agents; D007211:Indoles; D013449:Sulfonamides; D000077484:Vemurafenib; C078716:ROR1 protein, human; C078717:ROR2 protein, human; D057050:Receptor Tyrosine Kinase-like Orphan Receptors